OP0080 STAT3 DEGRADERS INHIBIT Th17 DEVELOPMENT AND CYTOKINE PRODUCTION RESULTING IN PROFOUND INHIBITION OF COLLAGEN-INDUCED AUTOIMMUNE MURINE ARTHRITIS
Authors: C. Hubeau, J. Sullivan, C. Brown, M. Mayo, V. Dixit, B. Enerson, H. Rong, B. Yang, C. De Savi, J. Gollob, N. Mainolfi, A. Slavin
Journal: Annals of the Rheumatic Diseases (2022)

Background Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that belongs to a class of targets devoid of catalytic function, thus deemed “undruggable” by standard modalities such as small molecule inhibitors or biologics. STAT3 can be activated by various receptor- and non-receptor tyrosine kinases, playing a critical role in activation pathways triggered by cytokines, hormones, and growth factors, making it an attractive target for the treatment of inflammatory diseases. Objectives Kymera has developed heterobifunctional molecules that selectively target STAT3 for degradation and elimination by the ubiquitin-proteasome pathway. We sought to evaluate the pharmacologic potential of these STAT3 degraders through in vitro and in vivo studies relevant to human autoimmune disease, including murine collagen-induced arthritis. Methods We evaluated the impact of STAT3 degraders on the activation of human monocytes, dermal fibroblasts, CD4+ T cells, and PBMC by LPS, IL-6/IL-6R, IL-21, IL-23, as well as anti-CD3/CD28 plus a cocktail of cytokines and antibodies. STAT3 degradation and pSTAT3 inhibition were determined in comparison to a JAK1/2 small molecule inhibitor. Inhibition of cytokines, chemokines, and collagen release, as well as Th17 (CD4+CD25-RORγt+CXCR6+) and Treg (CD4+CD25+CD127lowFOXP3+) expansion were used as in vitro efficacy assays. Finally, STAT3 degraders were tested in vivo, in a mechanistic (IL-6 challenge) as well as a disease model (murine CIA) relevant to rheumatology indications. Results STAT3 degraders showed broad and potent activity in-vitro against TLR receptor and cytokine-induced activation of immune and stromal cells, including soluble mediator release such as MCP-1/CCL2 and Collagen1a1. STAT3 degradation in CD4+ T cells robustly inhibited the development of Th17 cells, abrogating IL-17, IL-22, IL-8/CXCL8, and TNFα production, and increased Treg numbers in a manner superior to JAK1/2 inhibition. In mice injected with IL-6, plasma levels of serum amyloid A were dose-dependently suppressed by STAT3 degradation. In the murine collagen-induced arthritis model, STAT3 degradation resulted in robust, dose-dependent delay of disease onset and decreased disease incidence, clinical scores, local cytokine expression (paws) and histopathological scores, including the complete alleviation of periosteal bone growth. Conclusion These data demonstrate the broad activity of STAT3 degradation in alleviating autoimmune inflammation in models relevant to human disease. Targeted protein degradation of STAT3 thus represents a novel therapeutic approach to treating autoimmune/autoinflammatory diseases such as rheumatoid arthritis. Disclosure of Interests Cedric Hubeau Shareholder of: Kymera Therapeutics, Employee of: Kymera Therapeutics, Jeffrey Sullivan Shareholder of: Kymera Therapeutics, Employee of: Kymera Therapeutics, Crystal Brown Shareholder of: Kymera Therapeutics, Employee of: Kymera Therapeutics, Michele Mayo Shareholder of: Kymera Therapeutics, Employee of: Kymera Therapeutics, Vaishali Dixit Shareholder of: Kymera Therapeutics, Employee of: Kymera Therapeutics, Bradley Enerson Shareholder of: Kymera Therapeutics, Employee of: Kymera Therapeutics, Haojing Rong Shareholder of: Kymera Therapeutics, Employee of: Kymera Therapeutics, Bin Yang Shareholder of: Kymera Therapeutics, Employee of: Kymera Therapeutics, Chris De Savi Shareholder of: Kymera Therapeutics, Employee of: Kymera Therapeutics, Jared Gollob Shareholder of: Kymera Therapeutics, Employee of: Kymera Therapeutics, Nello Mainolfi Shareholder of: Kymera Therapeutics, Employee of: Kymera Therapeutics, Anthony Slavin Shareholder of: Kymera Therapeutics, Employee of: Kymera Therapeutics.